Blast-related traumatic brain injury (TBI), the signature injury of the Iraq and Afghanistan wars, affects 12- 23% of the 2.2 million U.S. servicemen and women deployed in these conflicts. Untold thousands of civilians are also affected in these and other conflict areas around the world. Blast exposure is a recognized precipitant of acute neurotrauma and secondary neuropsychiatric morbidity, including chronic traumatic encephalopathy (CTE). First reported in athletes with repetitive head injury, CTE is a tau protein-linked neurodegenerative disease with a distinctive pattern of perivascular phospho-tau pathology, disseminated microgliosis and astrocytosis, diffuse axonopathy, and widespread cortical neurodegeneration. Recent research conducted by our collaborative team at Boston University School of Medicine, NIH Alzheimer's Disease Center, and Boston VA has revealed evidence of early CTE neuropathology in the first case series of postmortem brains from blast-exposed U.S. military veterans. In addition, we have replicated CTE neuropathology and neurophysiological deficits in blast-exposed mice. Ultrastructural analysis of brains from blast-exposed mice demonstrated pervasive perivascular pathology, including disruption of blood-brain barrier (BBB) cytoarchitecture. Ongoing studies indicate that blast exposure induces focal BBB disruption in specific brain regions and structures vulnerable to CTE neuropathology. We hypothesize that blast exposure focally disrupts BBB structural organization and functional integrity leading to chronic neuroinflammation and neuropathological sequelae, including CTE. To test this hypothesis, we will use high-resolution metallomic imaging mass spectrometry (MIMS) to map BBB disruption as a function of blast exposure and CTE-linked neuropathology. This project will implement purpose-designed algorithms and software tools to analytically map focal BBB integrity across the brain at single-cell spatial resolution. Calibrated MIMS protocols will be used to localize and quantitate extravasation of systemically administered BBB-impermeable nanoreporter probes indicative of focal BBB disruption. These tools will be used in our validated murine blast neurotrauma model to evaluate temporal and regional patterns of BBB disruption as a function of blast dose, fractionation, and post-exposure interval. Results will be compared to BBB disruption patterns detected by conventional methods (Evans blue, HRP, brain edema) and correlated with pericapillary ultrastructural pathology and CTE- linked neuropathology. The results of these studies will advance understanding of fundamental mechanisms of brain injury in blast neurotrauma and provide critical information regarding the role of the BBB and microvascular disruption in the pathogenesis of blasted-related TBI and late-emerging sequelae, including CTE. Insights gained from this work will stimulate further development of MIMS technology for biomedical research and accelerate translational development of urgently needed diagnostics and therapeutics for blast-related TBI and CTE. PUBLIC HEALTH RELEVANCE: Exposure to explosive blasts is the leading cause of traumatic brain injury (TBI) and the signature injury of military deployments in Afghanistan and Iraq. Recent studies indicate that blast exposure disrupts the blood-brain barrier (BBB) and may play a significant role in the development of chronic traumatic encephalopathy (CTE), a tau-protein neurodegenerative disease associated with repetitive head injury. The proposed research will investigate the mechanistic and temporal effects of blast exposure on BBB integrity and development of CTE, thereby facilitating development of urgently needed diagnostics and therapeutics for blast neurotrauma and its aftermath.